Our recent studies suggest that prazosin - a safe, well-characterized, well-tolerated, orally active, inexpensive, FDA-approved 11-adrenergic receptor antagonist - may provide a much-needed breakthrough in the pharmacotherapeutic treatment of alcohol abuse and alcohol relapse. However, much work remains to be done to determine the most effective way to use prazosin and to determine how prazosin works to decrease alcohol drinking. Accordingly, one aim of the proposed work is to conduct translational studies to identify the conditions under which prazosin is most effective. These results are needed to guide the optimal design of clinical studies and treatment strategies in clinical settings. Another aim is to determine how prazosin works to decrease alcohol drinking. Together, these translational and mechanistic studies will provide needed information for the effective and efficient implementation of prazosin as a new pharmacotherapy for alcoholism and will provide insights that can guide the discovery and development of additional related pharmacotherapeutic agents. Our overall hypothesis has been that prazosin, and related agents that decrease brain noradrenergic signaling, will decrease ongoing alcohol drinking and drinking following alcohol abstinence, and may serve as new pharmacotherapies for the treatment of alcoholism and alcohol relapse. Our preliminary studies have demonstrated that prazosin: a) suppresses increased alcohol self- administration during acute withdrawal in alcohol-dependent rats; b) reduces voluntary alcohol drinking by selectively bred alcohol-preferring (P) rats; c) blocks deprivation-induced increases in alcohol drinking in P rats; and d) decreases relapse alcohol drinking in alcohol-dependent men. Using a well-characterized rodent model of high voluntary alcohol drinking (P rats), translational studies (Specific Aim 1) will identify factors influencing the most effective use of prazosin, including optimal dosing parameters, use of prazosin alone or in combination with naltrexone, phases of the alcohol addiction/relapse process that are sensitive to prazosin treatment (acquisition, maintenance, and re-access of drinking following alcohol abstinence), and population characteristics that predict responsiveness to prazosin treatment (gender and individual differences in anxiety, startle reactivity and stress history). Mechanistic studies (Specific Aim 2) will determine how prazosin works to decrease alcohol drinking by assessing whether prazosin alters alcohol clearance or the positively or negatively reinforcing properties of alcohol, and whether propranolol, which also decreases brain noradrenergic signaling - but by a different mechanism - also decreases alcohol drinking. Currently, clinical work on the effect of prazosin and other noradrenergic agents on alcohol abuse and alcoholism is in its infancy. The results of the proposed studies will be both timely and valuable in ensuring increased success in treating one of the most widespread of all addictive diseases in the United States. The proposed work also fulfills a key goal of the NIH roadmap, which is to increase translational, bench-to-bedside research. PUBLIC HEALTH RELEVANCE: Our goal is to develop effective pharmacotherapy for alcohol abuse, dependence and relapse. Using a well-characterized animal model of increased alcohol drinking, we will determine the most effective approaches to treating alcohol abuse with a safe and well-tolerated medication which is already in widespread clinical use for other conditions and which our preliminary studies demonstrate will be effective for treating alcohol drinking and relapse in at least some individuals. These studies will also provide the basis for development of additional related medications and paradigms for successfully treating alcohol abuse.